Hydromorphone and hydrocodone compositions and methods for their synthesis

ABSTRACT

A method for the preparation of a ketone from a narcotic alkaloid having an allyl alcohol moiety is disclosed. The method includes mixing the narcotic alkaloid with an acid in the presence of a catalyst wherein the method is carried out in the substantial absence of hydrogen gas. The method is useful for preparing hydromorphone and hydrocodone compositions having novel impurity profiles. Compositions comprising hydromorphone and hydrocodone are also disclosed.

RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional PatentApplications, Ser. Nos. 60/164,364, 60/164,505, and 60/164,536, eachentitled “Method of Synthesizing Hydromorphone and Hydrocodone,” andfiled on Nov. 9, 1999. The entire contents of each of these threeprovisional applications are hereby incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] Hydromorphone hydrochloride (sold as Dilaudid, Laudicon,Hydromorphan) is a narcotic analgesic and one of its principle uses isthe relief of pain (Physicians Desk Reference, p. 1383; Merck Index,4700). The precise mechanism of hydromorphone hydrochloride is notknown, although it is believed to relate to the existence of opiatereceptors in the central nervous system. There is no intrinsic limit tothe analgesic effect of hydromorphone hydrochloride; like morphine,adequate doses will relieve even the most severe pain.

[0003] Hydromorphone hydrochloride is also a centrally acting narcoticantitussive which acts directly on the cough reflex center. In addition,it produces drowsiness, changes in mood and mental clouding, depressesthe respiratory center, stimulates the vomiting center, producespinpoint constriction of the pupil, enhances parasympathetic activity,elevates cerabrospinal fluid pressure, increases biliary pressure andalso produces transient hyperglycemia.

[0004] Hydrocodone (dihydrocodeinone, Bekadid, Dicodid) is asemisynthetic narcotic antitussive and analgesic with multiple actionssimilar to those of codeine. Like hydromorphone and other opiatecompounds, the mechanism of action is not known. Hydrocodone can producemeoisis, euphoria, and physical and physiological dependence. Inexcessive doses, hydrocodone depresses respiration (Physicians DeskReference, p. 948).

[0005] The syntheses of hydromorphine and hydrocodeine are known in theart. For example, the formation of hydromorphine from morphine via roomtemperature hydrogenation of the double bond with colloidal palladiumand hydrogen gas is disclosed in German Patent 260 233. The patent alsodiscloses the formation of hydrocodeine. Yields of the hydrogenatedderivatives are not disclosed.

[0006] In United Kingdom Patent No. 285,404, the formation ofdihydrotheibane (a dimethyl ether derivative of dihydromorphine) at roomtemperature is disclosed, using platinum oxide as the catalyst. Themethyl groups can be removed to yield dihydromorphine. The yield isapproximately 55%.

[0007] The syntheses of hydrocodone and hydromorphone from codeine andmorphine, respectively, are also known in the art.

[0008] German Patent 380 919 discloses a method for synthesizinghydromorphone, by treating morphine with a catalytic agent (e.g.,platinum or palladium black), hydrochloric acid, and hydrogen gas. Thereaction mixture is then heated to 60 to 90° C. under a water pressureof 30 cm. The yield of the ketone is not disclosed.

[0009] German Patent 607 931 discloses the synthesis ofhydromorphinones. The synthesis involves heating morphine with largeamounts of finely divided platinum in dilute acid. The platinum catalystis saturated with hydrogen gas before the reaction is begun. It wasfound that additional hydrogen gas was not necessary for thehydrogenation to proceed. Yields from 40% to 85% were reported.

[0010] German Patent 617 238, a continuation-in-part of German Patent607 931, discloses that relatively higher yields of the hydromorphonescan be obtained through using smaller amounts of catalyst. The resultingyields ranged from 70% to 95% of the theoretical yield.

[0011] U.S. Pat. No. 2,544,291 discloses a process for the preparationof dihydrocodone by treating codeine with supported palladium catalystin a heated acidic solution. The reaction mixture is purified throughtreatment with activated alumina. The resulting product was recovered in66.5% yield and was determined to be “codeine free.”

[0012] U.S. Pat. No. 2,628,962 discloses the oxidation of dihydrocodeineto dihydrocodone by the addition of ketones to the reaction mixture inthe presence of aluminum alkoxides. The resulting yield was 36.5%.

[0013] U.S. Pat. No. 2,654,756, a continuation-in-part of U.S. Pat. No.2,628,962, discloses the use of ketones, such as cyclohexanone andalkoxycyclohexanones, to increase the yield of the narcotic ketones fromthe corresponding alcohols in the presence of aluminum alkoxides.However, the resulting yields were approximately 40%.

[0014] U.S. Pat. No. 2,649,454 discloses a method of producing ketonederivatives of opiates by heating the alcohols in the presence ofpotassium t-butoxide. The yields of the reaction ranged from 71-83%.

[0015] Most recently, it was reported that it was possible to formdihydroketones from narcotic alkaloids with colloidal platinum orpalladium as the catalyst. It was noted that if hydrogen was notintroduced, the reaction could be carried out in the presence of alarger amount of finely divided platinum. However, it was reported thatthe purest products or the most easily purified products were obtainedwhen the reaction was performed in a stream of hydrogen, rather than inthe absence of hydrogen (Gaal, C. M.T.A. Kemai Oszt. Kozl. 24:307-313(1965)).

SUMMARY OF THE INVENTION

[0016] In one aspect, the invention features a method of preparing aketone from a narcotic alkaloid having an allyl alcohol moiety. Themethod comprises mixing the narcotic alkaloid with an acid in thepresence of a catalyst in the substantial absence of hydrogen gas.Advantageously, the narcotic alkaloid is morphine, codeine or saltsthereof.

[0017] Preferably, the narcotic alkaloid is of formula (I):

[0018] wherein R is hydrogen or, an alcohol protecting moiety. In anadvantageous embodiment, R is hydrogen or methyl.

[0019] The invention also pertains to a hydromorphone composition thatis substantially free of impurities. In an advantageous embodiment, thecomposition comprises hydromorphone and from about 0.05% up to about1.0% dihydromorphine; up to about 0.1% morphine; up to about 0.8%8-hydroxy hydromorphone; up to about 0.5% bis-hydromorphone; and up toabout 0.2% other impurities.

[0020] In another aspect, the invention is directed to a method offorming a pharmaceutical composition comprising a hydromorphone salt,8-hydroxy hydromorphone and dihydromorphone. The method comprisesheating an aqueous mixture of the salt, 8-hydroxy hydromorphone anddihydromorphone for a time sufficient to reduce the concentration of8-hydroxy hydromorphone to less than 1.0%. In yet another aspect, theinvention is directed to a hydromorphone composition which is preparedby a process, which includes mixing morphine with an acid in thepresence of a catalyst wherein said process is carried out in thesubstantial absence of hydrogen gas.

DETAILED DESCRIPTION OF THE INVENTION

[0021] The invention pertains to a method of synthesizing ketonederivatives of narcotic alkaloids by mixing the narcotic alkaloid withan acid in the presence of a catalyst in the substantial absence ofhydrogen gas. The product obtained from the methods of the invention hasa novel composition profile, discussed in detail below.

1. DEFINITIONS

[0022] Before further description of the invention, certain termsemployed in the specification, examples and appended claims are, forconvenience, collected here.

[0023] The term “alcohol protecting moiety” includes moieties which canbe removed and/or derivatized after the formation of the ketone inaccordance with the methods of the invention to yield the free alcohol.Advantageously, the alcohol protecting moiety is inert to the conditionsused to generate the ketone. Alcohol protecting moieties include, butare not limited to, hydroxyl protecting groups known in the art (see,for example, Greene, T. W. Protective Groups in Organic Synthesis(Wiley:New York, 1981)). Examples include methoxymethyl ethers (MOM),β-methoxyethoxymethyl ethers (MEM), tetrahydropyranyl ethers (THP),methylthiomethyl ethers (MTM), benzyl groups, and silyl ethers (e.g.,trimethyl silyl ethers (TMS), t-butyldimethyl silyl ethers(TBDMS)).Furthermore, the term “alcohol protecting moiety” includes alkyl,alkenyl, alkynyl, aralkyl, aryl, and heteroaryl moieties.

[0024] The term “alkenyl” includes unsaturated aliphatic groupsanalogous in length and possible substitution to the alkyls describedbelow, but that contain at least one double bond. Unless the number ofcarbons is otherwise specified, “lower alkenyl” refers to an alkenylgroup, as defined above, but having from two to four carbon atoms in itsbackbone structure.

[0025] The term “alkyl” includes saturated aliphatic groups, includingstraight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl(alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkylsubstituted alkyl groups. The term alkyl further includes alkyl groups,which can further include heteroatoms replacing one or more carbons ofthe hydrocarbon backbone, e.g., oxygen, nitrogen, sulfur or phosphorousatoms. In one embodiment, a straight chain or branched chain alkyl has20 or fewer carbon atoms in its backbone (e.g., C₁-C₁₂ for straightchain, C₃-C₁₂ for branched chain). Examples of alkyl groups contemplatedby the invention include, but are not limited to, methyl, ethyl,isopropyl, isobutyl, tert-butyl, branched pentyl, branched hexyl,cyclohexyl, and cyclopentyl groups.

[0026] Moreover, the term alkyl includes both “unsubstituted alkyls” and“substituted alkyls”, the latter of which refers to alkyl moietieshaving substituents replacing a hydrogen on one or more carbons of thehydrocarbon backbone. Such substituents can include, for example,halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl,aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato,phosphinato, cyano, amino (including alkyl amino, dialkylamino,arylamino, diarylamino, and alkylarylamino), arylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Itwill be understood by those skilled in the art that the substituents onthe hydrocarbon chain can themselves be substituted, if appropriate.Cycloalkyls can be further substituted, e.g., with the substituentsdescribed above. An “alkylaryl” moiety is an alkyl substituted with anaryl (e.g., phenylmethyl (benzyl)). Unless the number of carbons isotherwise specified, “lower alkyl” refers to an alkyl group, as definedabove, but having from one to three carbon atoms in its backbonestructure. The terms “alkoxyalkyl”, “polyaminoalkyl” and“thioalkoxyalkyl” include alkyl groups, as described above, whichfurther include oxygen, nitrogen or sulfur atoms replacing one or morecarbons of the hydrocarbon backbone, e.g., oxygen, nitrogen or sulfuratoms.

[0027] The term “alkynyl” includes unsaturated aliphatic groupsanalogous in length and possible substitution to the alkyls describedabove, but that contain at least one triple bond. Unless the number ofcarbons is otherwise specified, “lower alkynyl” refers to an alkynylgroup, as defined above, but having from two to four carbon atoms in itsbackbone structure.

[0028] The term “allyl alcohol moiety” includes hydroxyl moietieslocated on allylic carbons, e.g., on carbons adjacent to double bonds.

[0029] The term “aryl” includes aryl groups, including 5- and 6-memberedsingle-ring aromatic groups that may include from zero to fourheteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole,benzoxazole, benzothiazole, triazole, tetrazole, pyrazole, pyridine,pyrazine, pyridazine and pyrimidine, and the like. Aryl groups alsoinclude polycyclic fused aromatic groups such as naphthyl, quinolyl,indolyl, and the like. Those aryl groups having heteroatoms in the ringstructure may also be referred to as “aryl heterocycles”, “heteroaryls”or “heteroaromatics”. The aromatic ring can be substituted at one ormore ring positions with such substituents as described above, as forexample, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate,phosphonato, phosphinato, cyano, amino (including alkyl amino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl,cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromaticmoiety. Aryl groups can also be fused or bridged with alicyclic orheterocyclic rings which are not aromatic so as to form a polycycle(e.g., tetralin). The term “aralkyl” includes alkyl groups substitutedwith at least one aryl group and aryl groups substituted with at leastone alkyl group.

[0030] The term “Deutsches Arzneibuch (‘DAB’) Test” refers to a batteryof tests for confirming the identification of and establishing a puritystandard for a pharmaceutical. A pharmaceutical is deemed to pass theDAB battery of tests in accordance with the following protocol:

[0031] Materials and Methods: For the DAB protocol, the test solution ismade by dissolving 1.25 g of the test substance in 25 mL of water.

PART 1: IDENTIFICATION

[0032] Characteristics: The test compound should be a white crystallinepowder; slightly soluble in water, soluble in about 30 parts 90%ethanol; and not very soluble in chloroform.

[0033] Test A: The Infrared (IR) Absorbtion Spectrum (Pharm. Eur. testV.6.18) of the precipitate from Test D is compared with the spectrum ofa pharmaceutical reference of known identity. Both the absorbtion maximaand the relative intensities are compared to reference spectra.

[0034] Test B: 2 to 3 mg of the test substance are dissolved in 3 ml ofice-cooled formaldehyde-sulfuric acid. The color of solution should turnfrom yellow to violet.

[0035] Test C: 1 mL of the test solution is diluted to 25 mL with water.To 5 mL of the diluted solution, is added 0.3 mL of potassium iodatesolution and 0.4 mL of 7% solution of hydrochloric acid. The solutionimmediately turns yellow. When 0.5 mL of a 10% ammonia solution isadded, the yellow color should become deeper.

[0036] Test D: 1 mL of a 10% ammoniac solution is added to 3 mL of thetest solution. After the solution was rubbed with a glass rod, a whitecrystalline precipitate is formed. The precipitate is washed with waterand dried at a temperature of 100 to 105° C. The precipitate should meltat a temperature between 263 and 268° C. (see Pharm. Eur. Test V.6.11.3,Melting Point-instantaneous method).

[0037] Test E: The filtrate of D should give the identity reaction ofchlorides (V.3.1.1).

PART 2: TESTING OF PURITY

[0038] Appearance of Test Solution: The test solution must be clear(V.6.1) and colorless (V.6.2., Method II).

[0039] Acidity or Alkalinity: 2 mL of the test solution should notdevelop a yellow color after the addition of 0.05 mL of methyl redsolution. Also, a 2 mL solution of the test solution should not developa yellow color after the addition of 0.05 mL of a Bromcresol greensolution.

[0040] Specific Optical Rotation (V.6.6): The optical rotation of thetest solution should be between −136.5° and −138.5° and should becalculated with reference to the dried substance.

[0041] Alkaloids without Phenolic Hydroxyl Group: 1.0 mL test solutionshould not become turbid after dilution with 1.2 mL water and dropwiseaddition of 1.2 mL of an 8.5% NaOH solution.

[0042] Reactivity with Sulphuric Acid (“Readlily Carbonizable SubstanceTest”): 20 mg of the test substance is dissolved in 5 mL of 96%sulphuric acid. After 5 minutes, the solution should not be morestrongly colored than the comparative solution BG6 (V.6.2, Method I).

[0043] Morphine and non-hydrated Morphine Related Substances: The testsolution from the “Reactivity with Sulphuric Acid” test should notbecome green or blue colored after the addition of 0.2 mL of Ferric(III)-chloride solution, and after heating in a water bath for 1 minute.

[0044] Loss on Drying: When 1.000 g of test substance is dried in anoven at 100 to 105° C., not more than 0.5% of the total weight should belost (V.6.22).

[0045] Sulphated Ash: Not more than 0.1%, as determined from 0.100 g ofthe test substance (V.3.2.14).

[0046] Assay: 0.200 g of test substance was dissolved in a mixture of 5mL of water, 30 mL of ethanol, and 10 mL of chloroform. After theaddition of 0.5 mL of Bromothymol Blue solution, the test substancesolution is titrated, with agitation, with a 0.1 N NaOH until thesolution turns light green.

[0047] 1 mL of 0.1 NaOH solution is equivalent to 32.18 mg ofC₁₇H₂₀ClNO₃.

[0048] One of the purity tests included in the DAB battery of tests isthe “Reactivity with Sulphuric Acid Test”, which is also known in theart as the “Readily Carbonizable Substances Test”.

[0049] The term “heteroatom” includes atoms of any element other thancarbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfurand phosphorus.

[0050] The terms “polycyclyl” or “polycyclic radical” refer to two ormore cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls,aryls and/or heterocyclyls) in which two or more carbons are common totwo adjoining rings, e.g., the rings are “fused rings”. Rings that arejoined through non-adjacent atoms are termed “bridged” rings. Each ofthe rings of the polycycle can be substituted with such substituents asdescribed above, as for example, halogen, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl,alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (includingalkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkyl, alkylaryl, or anaromatic or heteroaromatic moiety.

[0051] The term “narcotic alkaloid” includes organic nitrogenous basesand their salts. It includes alkaloids derived from opiates, e.g.,morphine and codeine. The term includes alkaloids containing allylicalcohols which advantageously may be converted to ketones using themethods of the invention.

[0052] The term “non-supported” includes catalysts which are notdeposited on a substrate (e.g., alumina, pumice or charcoal). Examplesof non-supported catalysts include palladium catalysts such as palladiumblack.

[0053] The term “substantial absence” of hydrogen gas refers to reactionconditions where the amount of hydrogen gas in the reaction vessel is,for example, less than 5%, less than 2%, or, preferably, less than 1%.

[0054] The term “substantially free of impurities” refers tocompositions of the invention containing impurities (e.g., in the caseof hydromorphone, reaction by-products including dihydromorphine,morphine, 8-hydroxy hydromorphone, bis-hydromorphone, and otherunspecified impurities) which are absent or present in the compositionin amounts such that the composition passes the Readily CarbonizableSubstances Test and/or the Deutsches Arzneibuch Test.

2. METHODS

[0055] The invention pertains, at least in part, to a method forpreparing a ketone from a narcotic alkaloid having an allyl alcoholmoiety. The method comprises mixing the narcotic alkaloid with an acidin the presence of a catalyst in the substantial absence of hydrogengas.

[0056] Scheme 1 shows an example of a synthetic method of the invention.(See Examples 1-4 below for a more detailed experimental discussion.)Briefly, water, concentrated HCl and activated palladium catalyst areadded to a reaction vessel under a nitrogen atmosphere and heated to 95°C. The narcotic alkaloid is then added and the reaction temperature ismaintained. After an hour, the reaction mixture is filtered to removethe catalyst and then cooled to 40° C. and sodium metabisulfite isadded. The solution is then allowed to cool to room temperature andstirred overnight. The sulfite adduct is then heated to reflux in waterwith activated charcoal. After approximately ten minutes, the activatedcharcoal is removed by filtration. Sodium carbonate is then added andthe pH of the solution is adjusted to above its pKa, preferably,9.0-9.5, with concentrated ammonium hydroxide. After stirring overnight,the suspension is filtered, converted to one of its salt, e.g., HClsalt, and the narcotic alkaloid ketone is dried under vacuum. In anotherembodiment of the invention, the sulfite adduct is heated for five hoursin deionized water (see Example 4) before the addition of sodiumcarbonate.

[0057] In one embodiment, the narcotic alkaloid comprises a compoundrepresented by formula (I):

[0058] wherein R is hydrogen or an alcohol protecting moiety.Preferably, R is alkyl (e.g, lower alkyl, more preferably methyl),aralkyl, or aryl. In one embodiment, the narcotic alkaloid is morphine(R═H) or codeine (R═CH₃), or a salt thereof. In another embodiment, thealcohol protecting moiety is removed upon formation of the ketone.

[0059] In another embodiment, the ketone comprises a compoundrepresented by the formula II:

[0060] wherein R is as defined above. Advantageously, R is H or CH₃.

[0061] In one embodiment, the ketone is hydromorphone or one of itssalts. In yet another embodiment, the method further comprises heatingthe mixture for a period of time sufficient to yield a hydromorphonecomposition comprising less than 1.0% 8-hydroxy hydromorphone.Preferably the period of time is greater than about thirty minutes, morepreferably greater than about three hours, and still more preferablygreater or equal to about five hours.

[0062] The hydromorphone composition prepared by the methods of theinvention is substantially free of impurities. In certain embodiments,the hydromorphone composition contains the following impurities: about0.05% dihydromorphine; about 0.0% morphine; about 0.0% 8-hydroxyhydromorphone; about 0.0% bis-hydromorphone; and about 0.0% otherimpurities. In yet other embodiments, the hydromorphone compositioncontains up to about 1.0% dihydromorphine; up to about 0.1% morphine; upto about 0.8% 8-hydroxy hydromorphone; up to about 0.5%bis-hydromorphone; and up to about 0.2% other impurities

[0063] In a further embodiment, the hydromorphone synthesized by methodsof the invention passes the Readily Carbonizable Substances Test and/orthe Deutsches Arzneibuch Test (see Example 5).

[0064] In another embodiment, the ketone is hydrocodone or one of itssalts. The hydrocodone prepared by the methods of the invention issubstantially free of impurities. In one embodiment, the hydrocodonesynthesized by methods of the invention passes the Readily CarbonizableSubstances Test and/or the Deutsches Arzneibuch Test (See Example 5).

[0065] The acid used in the methods of the invention can be any acidwhich allows for the formation of the ketone. Examples of suitable acidsinclude, but are not limited to carbonic acid, sulfuric acid, phosphoricacid, hydrobromic acid, acetic acid, and, preferably, hydrochloric acid.Many other suitable acids are well known in the art.

[0066] The catalyst used in the methods of the invention can be anycatalyst which catalyzes the formation of the ketone from the allylicacid alcohol of the narcotic alkaloid. Examples of suitable catalystsinclude, but are not limited to, platinum and, preferably, palladium. Ina preferred embodiment, an non-supported catalyst, e.g., palladiumblack, as opposed to a supported catalyst, e.g., palladium on alumina,pumice or charcoal, is used.

3. COMPOSITIONS

[0067] In another aspect, the invention features a compositioncomprising hydromorphine. The hydromorphone composition of the inventionis substantially free of impurities. In certain embodiments, thehydromorphone composition contains the following impurities: about 0.05%dihydromorphine; about 0.0% morphine; about 0.0% 8-hydroxyhydromorphone; about 0.0% bis-hydromorphone; and about 0.0% otherimpurities. In yet other embodiments, the hydromorphone compositioncontains up to about 1.0% dihydromorphine; up to about 0.1% morphine; upto about 0.8% 8-hydroxy hydromorphone; up to about 0.5%bis-hydromorphone; and up to about 0.2% other impurities

[0068] In a further embodiment, the composition contains from about0.05% up to about 0.5% dihydromorphine. In another embodiment, thecomposition contains up to about 0.05% morphine (e.g., from about 0.0%up to about 0.05% morphine). In yet another embodiment, the compositioncomprises up to about 0.5% 8-hydroxy hydromorphone (e.g., from about0.0% up to about 0.5% 8-hydroxy hydromorphone). In another embodiment,the composition contains up to about 0.05% bis-hydromorphone (e.g., fromabout 0.0% up to about 0.05% bis-hydromorphone). In a furtherembodiment, the composition contains up to about 0.1% other impurities(e.g., from about 0.0% up to about 0.1% other impurities).

[0069] Preferably, the composition comprises hydromorphone and fromabout 0.22% up to about 0.29% dihydromorphine; up to about 0.02%morphine (e.g., from about 0.0% up to about 0.02% morphine); from about0.04% up to about 0.05% 8-hydroxy hydromorphone; up to about 0.02%bis-hydromorphone (e.g., from about 0.0% up to about 0.02%bis-hydromorphone); and up to about 0.06% other impurities (e.g., fromabout 0.0% to about 0.06% other impurities).

[0070] In a particularly preferred embodiment, the composition compriseshydromorphone and about 0.26% dihydromorphine; about 0.01% morphine;about 0.04% 8-hydroxy hydromorphone; about 0.02% bis-hydromorphone; andabout 0.06% other impurities.

[0071] Preferably, the compositions of the invention passes the ReadilyCarbonizable Substances Test and/or the Deutsches Arzneibuch Test (seeExample 5). Advantageously, the invention pertains to a hydromorphonecomposition of the invention which is prepared by mixing morphine withan acid (e.g., hydrochloric acid) in the presence of a catalyst (e.g.,non-supported palladium) in the substantial absence of hydrogen gas.Methods of synthesizing the composition of the invention are discussedin Examples 1-4 and in Scheme 1. Preferably, the composition passes theReadily Carbonizable Substances Test and/or the Deutsches ArzneibuchTest.

4. PHARMACEUTICAL COMPOSITIONS

[0072] The invention also pertains to a method of forming apharmaceutical composition comprising a hydromorphone salt, 8-hydroxyhydromorphone and dihydromorphone. The method includes heating anaqueous mixture of the salt, 8-hydroxy hydromorphone and dihydromorphinefor a time sufficient to reduce the concentration of 8-hydroxyhydromorphone to less than 1.0%. In one embodiment, the time is greaterthan about thirty minutes, more preferably greater than about threehours, and still more preferably greater than or equal to about fivehours. In one embodiment, the salt is bisulfite. Advantageously, thepharmaceutical composition contains hydromorphone and about 0.05% up toabout 1.0% dihydromorphine; about 0.0% up to about 0.1% morphine; about0.0% up to about 0.8% 8-hydroxy hydromorphone; about 0.0% up to about0.5% bis-hydromorphone; and about 0.0% up to about 0.2% otherimpurities. Preferably, the composition passes the Readily CarbonizableSubstances Test and/or the Deutsches Arzneibuch Test (see Example 5).

Exemplification of the Invention

[0073] The invention is further illustrated by the following exampleswhich should not be construed as limiting. The palladium catalyst usedin the following examples was activated in accordance with the followingprocedure.

Palladium Activation Procedure

[0074] Palladium black (36.0 g) and deionized (DI) water (36.0 g) weresonicated to break down larger catalyst agglomerations. DI water (500mL) and concentrated HCl (120 mL) were added. The nitrogen flow wasadjusted to 1.4 mL/min and the suspension was heated. When thesuspension reached 50° C., the nitrogen flow was stopped and a hydrogenflow of 1.0 mL/min was initiated. The suspension was heated at 85° C.for two hours, cooled and filtered through Whatman #542 paper. Thepreparation of “hydrogen-free” catalyst used the same procedure, exceptfor the omission of hydrogen.

EXAMPLE 1 Synthesis of Hydromorphone Hydrochloride—“Current Process”

[0075] DI water (49.0 g), concentrated HCl (12.0 g), and activatedpalladium catalyst (3.6 g) were charged to the reactor. The reactor waspadded with nitrogen and heated to 50° C. The nitrogen was then turnedoff and the hydrogen flow was set to 0.2 mL/min. When the suspensionreached 95° C., morphine hydrate (40.0 g) was added to the reactor. Thereaction mixture was maintained at 95° C. for one hour. The reactionmixture was cooled to 40° C. and sodium metabisulfite (26.4 g) wasadded. The suspension was allowed to cool to room temperature andstirred overnight. The resulting sulfite adduct (30.3 g, dry weight; 59%yield) was filtered and dried under vacuum.

[0076] The sulfite adduct (30.0 g) and DI water (430 g) were heated toreflux and 0.2 g of activated charcoal was added. The activated charcoalwas filtered after fifteen minutes. Sodium carbonate (12.6 g) was addedto the filtrate and the pH of the solution was adjusted to 9.0 withconcentrated ammonium hydroxide (6 mL). After stirring overnight, thesuspension was filtered and the hydromorophone base (15.6 g, dry weight;41% yield) was dried under vacuum.

[0077] The hydromorphone base (15.0 g) was dissolved in methanol/DIwater (14 mL, 50/50 by volume) and concentrated HCl/water (10 mL, 50/50by volume). The solution was filtered and n-propanol (42 mL) was added.The suspension was stirred overnight, filtered, and vacuum dried. Thedried hydromorphone hydrochloride (12.9 g; 30% yield) contained 0.7%8-hydroxyhydromorphone and 0.1% dihydromorphine. The hydromorphonehydrochloride failed the Readily Carbonizable Substances test.

EXAMPLE 2 “Hydrogen Free” Synthesis

[0078] The above synthesis was repeated, except that hydrogen wasreplaced with nitrogen in the palladium black activation procedure andduring the reaction. The hydromorphone hydrochloride product wasobtained in the same yield and had the following impurity profile: 0.6%8-hydroxyhydromorphone and 0.2% dihydromorphine. The hydromorphonehydrochloride failed the Readily Carbonizable Substances Test.

EXAMPLE 3 “Extra Heating Time” Synthesis

[0079] Sulfite adduct was prepared using the current process usinghydrogen. This sulfite adduct (10.0 g) and DI water (140 g) were heatedto reflux for five hours. The solution was cooled and sodium carbonate(4.1 g) was added. The pH of the solution was adjusted to 8.8 withconcentrated ammonium hydroxide (1.8 mL). After stirring overnight, thesuspension was filtered, and the hydromorphone base (4.6 g, dry weight)was dried under vacuum.

[0080] The hydromorphone base (4.0 g) was dissolved in methanol/DI water(4 mL, 50/50 by volume) and concentrated HCl/water (3 mL, 50/50 byvolume). The solution was filtered and n-propanol (18 mL) was added. Thesuspension was stirred overnight, filtered, and vacuum dried. The driedhydromorphone hydrochloride (3.0 g) contained <0.1%8-hydroxyhydromorphone and 0.25 dihydromorphine. The hydromorphonehydrochloride passed the Readily Carbonizable Substances Test.

EXAMPLE 4 “Hydrogen Free/Extra Heating Time” Synthesis

[0081] Sulfite adduct was prepared without using hydrogen. The sulfiteadduct (12.0 g) and DI water (184 g) were heated to reflux for 5 hours.The solution was cooled and sodium carbonate (4.9 g) was added. The pHof the solution was adjusted to 8.8 with concentrated ammonium hydroxide(2 mL). After stirring overnight, the suspension was filtered and thehydromorphone base (6.4 g, dry weight) was dried under vacuum.

[0082] The hydromorphone base (6.0 g) was dissolved in methanol/DI water(6 mL, 50/50 by volume) and concentrated HCl/water (4.4 mL, 50/50 byvolume). The solution was filtered and n-propanol (27 mL) was added. Thesuspension was stirred overnight, filtered, and vacuum dried. The driedhydromorphone hydrochloride (5.1 g) contained <0.1%8-hydroxyhydromorphone and 0.25 dihydromorphine. The hydromorphonehydrochloride passed the Readily Carbonizable Substances Test.

EXAMPLE 5 HPLC Detection and Quantitation of Impurities

[0083] The detection and quantitation of impurities in hydromorphonecompositions is carried out using a gradient high pressure liquidchromatography (HPLC) method. An aqueous solution of the hydromorphonecomposition is injected onto a Waters Symmetry C18 column (3.9 mm×150mm) which contains 5 μm particles. A gradient elution is run at 1 mL perminute. Elution begins with eluent that contains 90% mobile phase A and10% mobile phase B, and ends, after a 40 minute run time, with eluentthat contains 20% mobile phase A and 80% mobile phase B. The mobilephase A includes 1 g of heptane sulfonic acid, 1 mL triethylamine, and90/10 water/methanol solvent to increase the volume of the solution to 1liter. The pH of mobile phase A is adjusted to 2.5 by the addition ofphosphoric acid. Mobile phase B is a 50/50 water/methanol mixture. ThepH of mobile phase B is adjusted to 2.5 with phosphoric acid. The methodis used to resolve and quantitate 8-hydroxyhydromorphone, morphine,dihydromorphine, hydromorphone N-oxide, hydromorphone, and2,2-bishydromorphone.

Incorporation by Reference

[0084] The entire contents of all patents, published patent applicationsand other references cited herein are hereby expressly incorporatedherein by reference

Equivalents

[0085] Those skilled in the art will recognize, or be able to ascertain,using no more than routine experimentation, many equivalents to specificembodiments of the invention described specifically herein. Suchequivalents are intended to be encompassed in the scope of the followingclaims.

1. A method of preparing a ketone from a narcotic alkaloid having anallyl alcohol moiety comprising mixing the narcotic alkaloid with anacid in the presence of a catalyst wherein the method is carried out inthe substantial absence of hydrogen gas.
 2. The method as recited inclaim 1, wherein the narcotic alkaloid comprises a compound representedby formula (I):

wherein r is hydrogen or an alcohol protecting moiety.
 3. The method ofclaim 2, wherein said alcohol protecting moiety is alkyl, aralkyl, oraryl.
 4. The method of claim 3, wherein R is hydrogen or CH₃.
 5. Themethod of claim 1, wherein said narcotic alkaloid is selected from thegroup consisting of morphine, codeine and salts thereof.
 6. The methodof claim 1, wherein said narcotic alkaloid is morphine or a saltthereof.
 7. The method of claim 1, wherein said narcotic alkaloid iscodeine or a salt thereof.
 8. The method of claim 2, wherein said ketoneis represented by formula II:


9. The method of claim 8, wherein R is hydrogen or CH₃.
 10. The methodof claim 8, wherein said ketone is hydromorphone or one of its salts.11. The method of claim 10, wherein said ketone is the bisulfite salt ofhydromorphone.
 12. The method of claim 8, wherein said ketone ishydrocodone or one of its salts.
 13. The method of claim 2, wherein saidalcohol protecting moiety is removed after the formation of the ketone.14. The method of claim 1, wherein said catalyst comprises non-supportedpalladium.
 15. The method of claim 1, wherein said acid is hydrochloricacid.
 16. A composition comprising hydromorphone and: a) from about0.05% up to about 1.0% dihydromorphine; b) up to about 0.1% morphine; c)up to about 0.8% 8-hydroxy hydromorphone; d) up to about 0.5%bis-hydromorphone; and e) up to about 0.2% other impurities.
 17. Thecomposition of claim 16, comprising from about 0.05% up to about 0.5%dihydromorphine.
 18. The composition of claim 16, comprising from about0.0% up to about 0.05% morphine.
 19. The composition of claim 16,comprising from about 0.0% up to about 0.5% 8-hydroxy hydromorphone. 20.The composition of claim 16, comprising from about 0.0% up to about0.05% bis-hydromorphone.
 21. The composition of claim 16, comprisingfrom about 0.0% up to about 0.1% other impurities.
 22. A compositioncomprising hydromorphone and: a) from about 0.22% up to about 0.29%dihydromorphine; b) up to about 0.02% morphine; c) from about 0.04% upto about 0.05% 8-hydroxy hydromorphone; d) up to about 0.02%bis-hydromorphone; and e) up to about 0.06% other impurities.
 23. Acomposition comprising hydromorphone and about 0.26% dihydromorphine;about 0.01% morphine; about 0.04% 8-hydroxy hydromorphone; about 0.02%bis-hydromorphone; and about 0.06% other impurities.
 24. The compositionof any one of claims 16, 22, or 23, wherein said composition is preparedby a process comprising mixing morphine with an acid in the presence ofa catalyst wherein said process is carried out in the substantialabsence of hydrogen gas.
 25. The composition of claim 24, wherein saidprocess further comprises heating said mixture for a period of timesufficient to yield a hydromorphone composition comprising less thanabout 1.0% 8-hydroxy hydromorphone.
 26. The composition of claim 25,wherein said period of time is sufficient to yield a hydromorphonecomposition comprising less than or equal to 2.0% dihydromorphone. 27.The composition of claim 25, wherein said time is greater than aboutthirty minutes.
 28. The composition of claim 25, wherein said time isgreater than or equal to about five hours.
 29. The composition of claim24, wherein said acid is hydrochloric acid and said catalyst isnon-supported palladium.
 30. A composition comprising hydromorphone,from about 0.05% up to about 1.0% of dihydromorphine, and one or morecompounds selected from the group consisting of morphine, 8-hydroxyhydromorphone, bis-hydromorphone, and other impurities.
 31. Ahydromorphone composition which is substantially free of impurities. 32.The composition of claim 31, which comprises: a) from about 0.05% up toabout 1.0% dihydromorphine; b) up to about 0.1% morphine; c) up to about0.8% 8-hydroxy hydromorphone; d) up to about 0.5% bis-hydromorphone; ande) up to about 0.2% other impurities.
 33. A method of forming apharmaceutical composition comprising a hydromorphone salt, 8-hydroxyhydromorphone and dihydromorphone by heating an aqueous mixture of saidsalt, 8-hydroxy hydromorphone and dihydromorphone for a time sufficientto reduce the concentration of 8-hydroxy hydromorphone to less thanabout 1.0%.
 34. The method of claim 33, wherein said time is sufficientto reduce the concentration of dihydromorphine to less than or equal toabout 2.0%.
 35. The method of claim 33, wherein said aqueous mixture isobtained by mixing morphine or a salt thereof with an acid in thepresence of a catalyst in the substantial absence of hydrogen gas. 36.The method of claim 35, wherein said catalyst comprises non-supportedpalladium.
 37. The method of claim 35, wherein said acid is hydrochloricacid.
 38. The method of claims 33, wherein the time is greater thanabout thirty minutes.
 39. The method of claim 38, wherein the time isgreater than or equal to about five hours.
 40. The method of claim 33,wherein said salt is bisulfite.
 41. The method of claim 33, wherein saidpharmaceutical composition comprises hydromorphone and: a) from about0.05% up to about 1.0% dihydromorphine; b) up to about 0.1% morphine; c)up to about 0.8% 8-hydroxy hydromorphone; d) up to about 0.5%bis-hydromorphone; and e) up to about 0.2% other impurities.
 42. Thecomposition of claim 31, wherein said composition is prepared by aprocess comprising heating an aqueous mixture of hydromorphone salt,8-hydroxy hydromorphone and dihydromorphone for a time sufficient toreduce the concentration of 8-hydroxy hydromorphone to less than about1.0%.
 43. The composition of claim 42, comprising hydromorphone and: a)from about 0.05% up to about 1.0% dihydromorphine; b) up to about 0.1%morphine; c) up to about 0.8% 8-hydroxy hydromorphone; d) up to about0.5% bis-hydromorphone; and e) up to about 0.2% other impurities. 44.The composition of claim 42, wherein said acid is hydrochloric acid andsaid catalyst is non-supported palladium.